Research Papers:

Region-specific alteration of histone modification by LSD1 inhibitor conjugated with pyrrole-imidazole polyamide

Kokiladevi Alagarswamy, Ken-Ichi Shinohara, Shihori Takayanagi, Masaki Fukuyo, Atsushi Okabe, Bahityar Rahmutulla, Natsumi Yoda, Rui Qin, Naoki Shiga, Masahiro Sugiura, Hiroaki Sato, Kazuko Kita, Takayoshi Suzuki, Tetsuhiro Nemoto and Atsushi Kaneda _

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Oncotarget. 2018; 9:29316-29335. https://doi.org/10.18632/oncotarget.25451

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Kokiladevi Alagarswamy1, Ken-Ichi Shinohara1, Shihori Takayanagi2, Masaki Fukuyo1, Atsushi Okabe1, Bahityar Rahmutulla1, Natsumi Yoda1, Rui Qin2, Naoki Shiga2, Masahiro Sugiura1, Hiroaki Sato1, Kazuko Kita1, Takayoshi Suzuki3, Tetsuhiro Nemoto2 and Atsushi Kaneda1

1Department of Molecular Oncology, School of Medicine, Chiba University, Chiba, Japan

2Department of Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

3Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

Correspondence to:

Atsushi Kaneda, email: [email protected]

Keywords: epigenome; histone modification; lysine-specific demethylase-1 inhibitor; pyrrole imidazole polyamide

Received: December 23, 2017     Accepted: May 07, 2018     Published: June 29, 2018


Epigenome regulates gene expression to determine cell fate, and accumulation of epigenomic aberrations leads to diseases, including cancer. NCD38 inhibits lysine-specific demethylase-1 (LSD1), a histone demethylase targeting H3K4me1 and H3K4me2, but not H3K4me3. In this study, we conjugated NCD38 with a potent small molecule called pyrrole (Py) imidazole (Im) polyamide, to analyze whether targets of the inhibitor could be regulated in a sequence-specific manner. We synthesized two conjugates using β-Ala (β) as a linker, i.e., NCD38-β-β-Py-Py-Py-Py (NCD38-β2P4) recognizing WWWWWW sequence, and NCD38-β-β-Py-Im-Py-Py (NCD38-β2PIPP) recognizing WWCGWW sequence. When RKO cells were treated with NCD38, H3K4me2 levels increased in 103 regions with significant activation of nearby genes (P = 0.03), whereas H3K4me3 levels were not obviously increased. H3K27ac levels were also increased in 458 regions with significant activation of nearby genes (P = 3 × 10−10), and these activated regions frequently included GC-rich sequences, but less frequently included AT-rich sequences (P < 1 × 10−15) or WWCGWW sequences (P = 2 × 10−13). When treated with NCD38-β2P4, 234 regions showed increased H3K27ac levels with significant activation of nearby genes (P = 2 × 10−11), including significantly fewer GC-rich sequences (P < 1 × 10−15) and significantly more AT-rich sequences (P < 1 × 10−15) compared with NCD38 treatment. When treated with NCD38-β2PIPP, 82 regions showed increased H3K27ac levels, including significantly fewer GC-rich sequences (P = 1 × 10−11) and fewer AT-rich sequences (P = 0.005), but significantly more WWCGWW sequences (P = 0.0001) compared with NCD38 treatment. These indicated that target regions of epigenomic inhibitors could be modified in a sequence-specific manner and that conjugation of Py-Im polyamides may be useful for this purpose.

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